The transition from non-alcoholic fatty liver disease (NAFLD) to metabolic dysfunction–associated steatotic liver disease (MASLD) represents more than a semantic change—it reframes fatty liver disease through the lens of metabolic dysfunction, enabling improved diagnostic precision, risk stratification, and global research harmonization. By recognizing metabolic drivers rather than alcohol exclusion alone, MASLD captures a broader clinical spectrum, including lean individuals with hepatic steatosis, and better reflects the disease’s multifactorial nature.
MASLD is now the most prevalent chronic liver disease worldwide and demonstrates striking sex- and age-related differences in prevalence, progression, and outcomes. Men exhibit higher MASLD prevalence during reproductive years and are more prone to hepatocellular carcinoma (HCC), while women—particularly after menopause—experience accelerated progression to metabolic dysfunction–associated steatohepatitis (MASH) and fibrosis. Estrogen plays a central hepatoprotective role by reducing lipogenesis, enhancing fatty acid oxidation, improving insulin sensitivity, and dampening inflammation. Its decline after menopause shifts fat distribution toward visceral depots, increases metabolic risk, and narrows—or reverses—the sex gap in disease prevalence.
Conversely, androgen imbalance contributes to MASLD risk in both sexes: testosterone deficiency in men and androgen excess in women (notably in polycystic ovary syndrome) promote insulin resistance, central adiposity, and hepatic steatosis. Genetic susceptibility (e.g., PNPLA3, TM6SF2 variants), immune dimorphism, gut microbiota alterations, and sociocultural factors such as diet and physical activity further modulate disease trajectories.
Notably, although women generally develop MASLD later than men, once established, they are more likely to progress to advanced fibrosis—especially after 50 years of age. These findings highlight the inadequacy of a “one-size-fits-all” approach and underscore the need for sex-specific prevention, surveillance, and therapeutic strategies.
Engagement question:
Should sex-specific hormonal, metabolic, and genetic profiling become a routine component of MASLD risk assessment and management?
MBH/AB